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Single gene deletion prompts mutations throughout genome

Published
Friday 22 November 2013 Published Fri 22 Nov 2013

By Marie Ellis

Jenga, a game with wooden blocks stacked upon one another, requires that players remove single parts from the whole structure, sometimes resulting in an imbalance. Similarly, researchers have found that the deletion of a single gene in yeast cells can put pressure on the genome to offset the imbalance, resulting in another gene's mutation.

The team, from Johns Hopkins University in Maryland, says this could have major consequences for how genetic analysis is done in humans.

Because of the way DNA is conserved across species, the researchers say their findings - published in the journal Molecular Cell - could be applicable to human genetics, particularly for certain areas of research, such as cancer.

Their research adds new evidence that genomes - the sum of species' genes - operate in an interconnected way so that the removal of a single part could stress the whole system, prompting another part to mutate as a result.

J. Marie Hardwick, professor of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health, says:

"The deletion of any given gene usually results in one, or sometimes two, specific genes being 'warped' in response. Pairing the originally deleted gene with the gene that was secondarily mutated gave us a list of gene interactions that were largely unknown before."

She says this work "has the potential to transform the field of cancer genetics," noting that it would encourage researchers to have greater scrutiny in genetic analyses, as they could unknowingly ascribe something to a gene they mutated, whereas it could be due to a secondary mutation.

Secondary mutations affect cell survival

Deletion of one gene causes instability in the genome, prompting another gene to mutate to offset the imbalance. Image credit: Xinchen Teng

Hardwick and her team worked with yeast because it is easy to "knock out" or delete any particular gene. They wanted to know whether within a given strain of yeast, each cell has the same genetic sequence as the other cells, as was previously thought.

"We know, for example, that within a given tumor, different cells have different mutations or versions of a gene" Hardwick says. "So it seemed plausible that other cell populations would exhibit a similar genetic diversity."

After randomly choosing 250 single-knockout yeast strains, the team generated six sub-strains that were derived from a single yeast cell in the original batch. Following from this, they put each sub-strain through a "stress test."

When they gradually increased the temperature for a few minutes, they noticed some sub-strains died because they could not take the stress.

Then, when they examined the genes, they found that each of the sub-strains that died also had a mutation in another gene, which led them to conclude that the cells in each strain of the single-gene knockouts do not all share an identical genetic sequence.

Overall, they found that 77% of all the knockout strains acquired one or two subsequent mutations that affect cell survival or excessive growth.

In effect, mutation of a single gene could cause a "genomic imbalance, with consequences sufficient to drive adaptive genetic changes."

Potential to identify 'first mutations in tumors'

The field of cancer genetics could soon be transformed by these findings, says Hardwick:

"We had been thinking of cancer as progressing from an initial mutation in a tumor-suppressor gene, followed by additional mutations that help the cancer thrive. Our work provides hard evidence that a single one of those 'additional mutations' might come first and actively provoke the mutations seen in tumor-suppressor genes."

She and her colleagues believe that they may find an even higher percentage of double-mutant strains by stressing yeast in other ways.

"Essentially a gene, when mutated, has the power to alter other genes in the genome," Hardwick adds.

She notes that, surprisingly, the sub-strains' altered growth was most frequently due to the secondary mutations, not the original knockout, and most of those secondary mutations were in genes that are cancer-causing in humans.

Hardwick and her team hope their "findings in yeast will help to identify these 'first' mutations in tumors."

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